Accurate risk assessment is essential for the success of population screening programs in breast cancer. Models with high sensitivity and specificity would enable programs to target more elaborate ...screening efforts to high-risk populations, while minimizing overtreatment for the rest. Artificial intelligence (AI)-based risk models have demonstrated a significant advance over risk models used today in clinical practice. However, the responsible deployment of novel AI requires careful validation across diverse populations. To this end, we validate our AI-based model, Mirai, across globally diverse screening populations.
We collected screening mammograms and pathology-confirmed breast cancer outcomes from Massachusetts General Hospital, USA; Novant, USA; Emory, USA; Maccabi-Assuta, Israel; Karolinska, Sweden; Chang Gung Memorial Hospital, Taiwan; and Barretos, Brazil. We evaluated Uno's concordance index for Mirai in predicting risk of breast cancer at one to five years from the mammogram.
A total of 128,793 mammograms from 62,185 patients were collected across the seven sites, of which 3,815 were followed by a cancer diagnosis within 5 years. Mirai obtained concordance indices of 0.75 (95% CI, 0.72 to 0.78), 0.75 (95% CI, 0.70 to 0.80), 0.77 (95% CI, 0.75 to 0.79), 0.77 (95% CI, 0.73 to 0.81), 0.81 (95% CI, 0.79 to 0.82), 0.79 (95% CI, 0.76 to 0.83), and 0.84 (95% CI, 0.81 to 0.88) at Massachusetts General Hospital, Novant, Emory, Maccabi-Assuta, Karolinska, Chang Gung Memorial Hospital, and Barretos, respectively.
Mirai, a mammography-based risk model, maintained its accuracy across globally diverse test sets from seven hospitals across five countries. This is the broadest validation to date of an AI-based breast cancer model and suggests that the technology can offer broad and equitable improvements in care.
Regardless the regulatory function of microRNAs (miRNA), their differential expression pattern has been used to define miRNA signatures and to disclose disease biomarkers. To address the question of ...whether patients presenting the different types of diabetes mellitus could be distinguished on the basis of their miRNA and mRNA expression profiling, we obtained peripheral blood mononuclear cell (PBMC) RNAs from 7 type 1 (T1D), 7 type 2 (T2D), and 6 gestational diabetes (GDM) patients, which were hybridized to Agilent miRNA and mRNA microarrays. Data quantification and quality control were obtained using the Feature Extraction software, and data distribution was normalized using quantile function implemented in the Aroma light package. Differentially expressed miRNAs/mRNAs were identified using Rank products, comparing T1DxGDM, T2DxGDM and T1DxT2D. Hierarchical clustering was performed using the average linkage criterion with Pearson uncentered distance as metrics.
The use of the same microarrays platform permitted the identification of sets of shared or specific miRNAs/mRNA interaction for each type of diabetes. Nine miRNAs (hsa-miR-126, hsa-miR-1307, hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-144, hsa-miR-199a-5p, hsa-miR-27a, hsa-miR-29b, and hsa-miR-342-3p) were shared among T1D, T2D and GDM, and additional specific miRNAs were identified for T1D (20 miRNAs), T2D (14) and GDM (19) patients. ROC curves allowed the identification of specific and relevant (greater AUC values) miRNAs for each type of diabetes, including: i) hsa-miR-1274a, hsa-miR-1274b and hsa-let-7f for T1D; ii) hsa-miR-222, hsa-miR-30e and hsa-miR-140-3p for T2D, and iii) hsa-miR-181a and hsa-miR-1268 for GDM. Many of these miRNAs targeted mRNAs associated with diabetes pathogenesis.
These results indicate that PBMC can be used as reporter cells to characterize the miRNA expression profiling disclosed by the different diabetes mellitus manifestations. Shared miRNAs may characterize diabetes as a metabolic and inflammatory disorder, whereas specific miRNAs may represent biological markers for each type of diabetes, deserving further attention.
Abstract
Background
Acute gastroenteritis (AGE) burden, etiology, and severity in adults is not well characterized. We implemented a multisite AGE surveillance platform in 4 Veterans Affairs Medical ...Centers (Atlanta, Georgia; Bronx, New York; Houston, Texas; and Los Angeles, California), collectively serving >320 000 patients annually.
Methods
From 1 July 2016 to 30 June 2018, we actively identified inpatient AGE case patients and non-AGE inpatient controls through prospective screening of admitted patients and passively identified outpatients with AGE through stool samples submitted for clinical diagnostics. We abstracted medical charts and tested stool samples for 22 pathogens by means of multiplex gastrointestinal polymerase chain reaction panel followed by genotyping of norovirus- and rotavirus-positive samples. We determined pathogen-specific prevalence, incidence, and modified Vesikari severity scores.
Results
We enrolled 724 inpatients with AGE, 394 non-AGE inpatient controls, and 506 outpatients with AGE. Clostridioides difficile and norovirus were most frequently detected among inpatients (for AGE case patients vs controls: C. difficile, 18.8% vs 8.4%; norovirus, 5.1% vs 1.5%; P < .01 for both) and outpatients (norovirus, 10.7%; C. difficile, 10.5%). The incidence per 100 000 population was highest among outpatients (AGE, 2715; C. difficile, 285; norovirus, 291) and inpatients ≥65 years old (AGE, 459; C. difficile, 91; norovirus, 26). Clinical severity scores were highest for inpatient norovirus, rotavirus, and Shigella/enteroinvasive Escherichia coli cases. Overall, 12% of inpatients with AGE had intensive care unit stays, and 2% died; 3 deaths were associated with C. difficile and 1 with norovirus. C. difficile and norovirus were detected year-round with a fall/winter predominance.
Conclusions
C. difficile and norovirus were leading AGE pathogens in outpatient and hospitalized US veterans, resulting in severe disease. Clinicians should remain vigilant for bacterial and viral causes of AGE year-round.
We prospectively enrolled patients with acute gastroenteritis (AGE) at 4 Veterans Affairs Medical Centers over a 2-year period. Clostridioides difficile and norovirus were leading AGE pathogens in outpatients and inpatients and resulted in severe disease, intensive care unit stays, and deaths.
The complexity, and the diversity of the different types of cancers allied to the tendency to form metastasis make treatment efficiency so tricky and often impossible due to the advanced stage of the ...disease in the diagnosis. In recent years, due to tremendous scientific breakthroughs, we have witnessed exponential growth in the elucidation of mechanisms that underlie carcinogenesis and metastasis. The development of more selective therapies made it possible to improve cancer treatment. Although interdisciplinary research leads to encouraging results, scientists still have a long exploration journey. RNA technology represents a promise as a therapeutic intervention for targeted gene silencing in cancer, and there are already some RNA-based formulations in clinical trials. However, the use of RNA as a therapeutic tool presents severe limitations, mainly related to its low stability and poor cellular uptake. Thus, the use of nanomedicine employing nanoparticles to encapsulate RNA may represent a suitable platform to address the major challenges hampering its therapeutic application. In this review, we have revisited the potential of RNA and RNA-associated therapies to fight cancer, also providing, as support, a general overview of nanoplatforms for RNA delivery.
Type 1 diabetes mellitus (T1DM) results from an autoimmune attack against the insulin-producing pancreatic β-cells, leading to elimination of insulin production. The exact cause of this disorder is ...still unclear. Although the differential expression of microRNAs (miRNAs), small non-coding RNAs that control gene expression in a post-transcriptional manner, has been identified in many diseases, including T1DM, only scarce information exists concerning miRNA expression profile in T1DM. Thus, we employed the microarray technology to examine the miRNA expression profiles displayed by peripheral blood mononuclear cells (PBMCs) from T1DM patients compared with healthy subjects. Total RNA extracted from PBMCs from 11 T1DM patients and nine healthy subjects was hybridized onto Agilent human miRNA microarray slides (V3), 8x15K, and expression data were analyzed on R statistical environment. After applying the rank products statistical test, the receiver-operating characteristic (ROC) curves were generated and the areas under the ROC curves (AUC) were calculated. To examine the functions of the differentially expressed (p-value<0.01, percentage of false-positives <0.05) miRNAs that passed the AUC cutoff value ≥0.90, the database miRWalk was used to predict their potential targets, which were afterwards submitted to the functional annotation tool provided by the Database for Annotation, Visualization, and Integrated Discovery (DAVID), version 6.7, using annotations from the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. We found 57 probes, corresponding to 44 different miRNAs (35 up-regulated and 9 down-regulated), that were differentially expressed in T1DM and passed the AUC threshold of 0.90. The hierarchical clustering analysis indicated the discriminatory power of those miRNAs, since they were able to clearly distinguish T1DM patients from healthy individuals. Target prediction indicated that 47 candidate genes for T1DM are potentially regulated by the differentially expressed miRNAs. After performing functional annotation analysis of the predicted targets, we observed 22 and 12 annotated KEGG pathways for the induced and repressed miRNAs, respectively. Interestingly, many pathways were enriched for the targets of both up- and down-regulated miRNAs and the majority of those pathways have been previously associated with T1DM, including many cancer-related pathways. In conclusion, our study indicated miRNAs that may be potential biomarkers of T1DM as well as provided new insights into the molecular mechanisms involved in this disorder.
•A set of 44 miRNAs clearly distinguished T1DM patients from healthy subjects.•Putative candidate genes for T1DM are among the potential targets of the 44 miRNAs.•Several KEGG pathways were enriched for the predicted targets of the 44 miRNAs.•Many pathways were possibly regulated by both up- and down-regulated miRNAs.•Dysregulation of miRNA expression and their functions might be involved in T1DM.
Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing β-cells leading to impaired insulin secretion and hyperglycemia. T1D is accompanied by DNA damage, oxidative ...stress, and inflammation, although there is still scarce information about the oxidative stress response and DNA repair in T1D pathogenesis. We used the microarray method to assess mRNA expression profiles in peripheral blood mononuclear cells (PBMCs) of 19 T1D patients compared to 11 controls and identify mRNA targets of microRNAs that were previously reported for T1D patients. We found 277 differentially expressed genes (220 upregulated and 57 downregulated) in T1D patients compared to controls. Analysis by gene sets (GSA and GSEA) showed an upregulation of processes linked to ROS generation, oxidative stress, inflammation, cell death, ER stress, and DNA repair in T1D patients. Besides, genes related to oxidative stress responses and DNA repair (PTGS2, ATF3, FOSB, DUSP1, and TNFAIP3) were found to be targets of four microRNAs (hsa-miR-101, hsa-miR148a, hsa-miR-27b, and hsa-miR-424). The expression levels of these mRNAs and microRNAs were confirmed by qRT-PCR. Therefore, the present study on differential expression profiles indicates relevant biological functions related to oxidative stress response, DNA repair, inflammation, and apoptosis in PBMCs of T1D patients relative to controls. We also report new insights regarding microRNA-mRNA interactions, which may play important roles in the T1D pathogenesis.
Patients with type 2 diabetes mellitus (T2DM) exhibit insulin resistance associated with obesity and inflammatory response, besides an increased level of oxidative DNA damage as a consequence of the ...hyperglycemic condition and the generation of reactive oxygen species (ROS). In order to provide information on the mechanisms involved in the pathophysiology of T2DM, we analyzed the transcriptional expression patterns exhibited by peripheral blood mononuclear cells (PBMCs) from patients with T2DM compared to non-diabetic subjects, by investigating several biological processes: inflammatory and immune responses, responses to oxidative stress and hypoxia, fatty acid processing, and DNA repair. PBMCs were obtained from 20 T2DM patients and eight non-diabetic subjects. Total RNA was hybridized to Agilent whole human genome 4×44K one-color oligo-microarray. Microarray data were analyzed using the GeneSpring GX 11.0 software (Agilent). We used BRB-ArrayTools software (gene set analysis — GSA) to investigate significant gene sets and the Genomica tool to study a possible influence of clinical features on gene expression profiles. We showed that PBMCs from T2DM patients presented significant changes in gene expression, exhibiting 1320 differentially expressed genes compared to the control group. A great number of genes were involved in biological processes implicated in the pathogenesis of T2DM. Among the genes with high fold-change values, the up-regulated ones were associated with fatty acid metabolism and protection against lipid-induced oxidative stress, while the down-regulated ones were implicated in the suppression of pro-inflammatory cytokines production and DNA repair. Moreover, we identified two significant signaling pathways: adipocytokine, related to insulin resistance; and ceramide, related to oxidative stress and induction of apoptosis. In addition, expression profiles were not influenced by patient features, such as age, gender, obesity, pre/post-menopause age, neuropathy, glycemia, and HbA1c percentage. Hence, by studying expression profiles of PBMCs, we provided quantitative and qualitative differences and similarities between T2DM patients and non-diabetic individuals, contributing with new perspectives for a better understanding of the disease.
► PBMCs from T2DM patients present differential gene expression compared to controls. ► Induced genes are related to FA metabolism, protection against oxidative stress. ► Repressed genes are related to suppression of cytokines production, DNA repair. ► Two significant signaling pathways were identified: adipocytokine and ceramide. ► Patient features have no influence on expression profiles.
The development of type 2 diabetes mellitus (T2D) is associated with a number of genetic and environmental factors. Hyperglycemia, a T2D hallmark, is related to several metabolic complications, ...comorbidities and increased DNA damage. However, the molecular alterations of a proper glucose control are still unclarified. In this study, we aimed to evaluate DNA damage (comet assay), as well as to compare the transcriptional expression (mRNA and miRNA analyzed by the microarray technique) displayed by peripheral blood mononuclear cells (PBMCs) from three distinct groups: hyperglycemic T2D patients (T2D-H, n=14), non-hyperglycemic T2D patients (T2D-N, n=15), and healthy non-diabetic individuals (n=16). The comet assay revealed significantly (p<0.05) higher levels of DNA damage in T2D-H group compared to both T2D-N and control groups, while a significant difference was not observed between the control and T2D-N groups. After bioinformatics analysis, the differentially expressed mRNAs were subjected to functional enrichment analysis (DAVID) and inflammatory response was among the enriched terms found when comparing T2D-N with controls and T2D-H with T2D-N. Concerning the gene set enrichment and gene set analyses, among the differentially expressed gene sets, three were of interest: regulation of DNA repair (T2D-H versus T2D-N), superoxide response (T2D-H versus control group), and response to endoplasmic reticulum stress (T2D-H versus control group). We also identified miRNAs related with T2D and hyperglycemia not yet associated with these conditions in the literature. Some of the differentially expressed mRNAs were among the predicted targets of the differentially expressed miRNAs. Our results showed the association of hyperglycemia with increased DNA damage and aberrant expression of miRNAs and genes related to several biological processes, such as inflammation, DNA repair, ROS production and antioxidant defense, highlighting the importance of proper glycemic control. Moreover, the transcriptional expression of miRNAs provided novel information for understanding the regulatory mechanisms involved in the T2D progression.
Parvovirus B19 infection is associated with a wide range of clinical manifestations, from asymptomatic to severe neurological disorders. Its major clinical symptoms, fever and rash, are common to ...multiple viruses, and laboratory tests to detect B19 are frequently not available. Thus, the impact of B19 on public health remains unclear. We report the case of a 38-day old girl admitted to São Paulo Clinical Hospital, Brazil, with an initial diagnosis of bacterial meningitis, seizures, and acute hydrocephalus. Antibiotic therapy was maintained for one week after admission and discontinued after negative laboratory results were obtained. Nine days after symptoms onset, a cerebral spinal fluid (CSF) sample revealed persistent pleocytosis. The complete B19 complete genome was subsequently identified in her CSF by a metagenomic next-generation sequencing approach. This report highlights the possible involvement of B19 in the occurrence of acute neurological manifestations and emphasizes that its possible involvement might be better revealed by the use of metagenomic technology to detect viral agents in clinical situations of unknown or uncertain etiology.
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